Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss

Abstract

The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation-a "fine-tuning" process-for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens.

Genome-scale metabolic reconstructions of multiple Escherichia coli strains highlight strain-specific adaptations to nutritional environments

“…This computational result supports evidence showing that Shigella strains have lost catabolic pathways for many nutrient sources (22). Models of Shigella strains completely lost the capability to sustain growth on nutrient sources for which more than 90% of E. coli models had growth capabilities.…”

Shigella reroutes host cell central metabolism to obtain high-flux nutrient supply for vigorous intracellular growth

“…Taken together, a short metabolic pathway that is commonly present in many bacteria enables Shigella to efficiently exploit major nutrient supply routes in infected host cells. This preadaptation might explain why Shigella can thrive as a voracious pathogen with only minor metabolic adaptations to the host cell intracellular environment compared with closely related extracellular commensals (33,35). In addition to the major energy source pyruvate, Shigella accessed diverse host metabolites for direct biomass incorporation.…”

Helicobacter pylori Salvages Purines from Extracellular Host Cell DNA Utilizing the Outer Membrane-Associated Nuclease NucT

“…In this time, the bacterium has become reliant on its human host, and the resulting effects of this niche-specific evolutionary strategy can be seen in the metabolic machinery encoded by the bacterial genome. Similar to the genetic phenomenon observed in many intracellular bacterial commensals (7), pathogens (8), and parasites (9,10), bioinformatic studies show that gene loss has played a major role in the evolutionary history of H. pylori as well as other members of the epsilonproteobacteria (11,12). Missing pathway elements in the H. pylori genome indicate an adaptation from an early terrestrial ancestor to the human niche that may be the result of the bacterium obtaining its nutrients directly from its human host.…”